CLINICAL TRIAL
published: 22 March 2021
Edited by:
Leanne M. Redman,
Pennington Biomedical Research
Center, United States
Reviewed by:
Yao Wang,
University of California, San Francisco,
United States
Vegard Lysne,
Haukeland University
Hospital, Norway
*Correspondence:
Amanda Sainsbury
amanda.salis@uwa.edu.au
† These authors have contributed
equally to this work and share first
authorship
Specialty section:
This article was submitted to
Nutrition and Metabolism,
a section of the journal
Frontiers in Nutrition
Received: 11 December 2020
Accepted: 12 February 2021
Published: 22 March 2021
Citation:
Buso MEC, Seimon RV, McClintock S,
Muirhead R, Atkinson FS, Brodie S,
Dodds J, Zibellini J, Das A,
Wild-Taylor AL, Burk J, Fogelholm M,
Raben A, Brand-Miller JC and
Sainsbury A (2021) Can a Higher
Protein/Low Glycemic Index vs. a
Conventional Diet Attenuate Changes
in Appetite and Gut Hormones
Following Weight Loss? A 3-Year
PREVIEW Sub-study.
Front. Nutr. 8:640538.
doi: 10.3389/fnut.2021.640538
Frontiers in Nutrition | www.frontiersin.org
doi: 10.3389/fnut.2021.640538
Can a Higher Protein/Low Glycemic
Index vs. a Conventional Diet
Attenuate Changes in Appetite and
Gut Hormones Following Weight
Loss? A 3-Year PREVIEW Sub-study
Marion E.C. Buso 1,2† , Radhika V. Seimon 2† , Sally McClintock 2 , Roslyn Muirhead 3 ,
Fiona S. Atkinson 3 , Shannon Brodie 3 , Jarron Dodds 2 , Jessica Zibellini 2 , Arpita Das 3 ,
Anthony L. Wild-Taylor 2 , Jessica Burk 2 , Mikael Fogelholm 4 , Anne Raben 5,6 ,
Jennie C. Brand-Miller 3 and Amanda Sainsbury 7*
1
Division of Human Nutrition and Health, Wageningen University, Wageningen, Netherlands, 2 The Boden Collaboration for
Obesity, Nutrition, Exercise, and Eating Disorders, Faculty of Medicine and Health, Charles Perkins Centre, The University of
Sydney, Camperdown, NSW, Australia, 3 School of Life and Environmental Sciences and Charles Perkins Centre, The
University of Sydney, Camperdown, NSW, Australia, 4 Department of Food and Environmental Sciences, University of
Helsinki, Helsinki, Finland, 5 Department of Nutrition, Exercise and Sports, University of Copenhagen, Copenhagen, Denmark,
6
Steno Diabetes Center Copenhagen, Copenhagen, Denmark, 7 School of Human Sciences, Faculty of Science, The
University of Western Australia, Crawley, WA, Australia
Background: Previous research showed that weight-reducing diets increase appetite
sensations and/or circulating ghrelin concentrations for up to 36 months, with transient
or enduring perturbations in circulating concentrations of the satiety hormone peptide YY.
Objective: This study assessed whether a diet that is higher in protein and low in
glycemic index (GI) may attenuate these changes.
Methods: 136 adults with pre-diabetes and a body mass index of ≥25 kg/m2
underwent a 2-month weight-reducing total meal replacement diet. Participants who lost
≥8% body weight were randomized to one of two 34-month weight-maintenance diets: a
higher-protein and moderate-carbohydrate (CHO) diet with low GI, or a moderate-protein
and higher-CHO diet with moderate GI. Both arms involved recommendations to increase
physical activity. Fasting plasma concentrations of total ghrelin and total peptide YY,
and appetite sensations, were measured at 0 months (pre-weight loss), at 2 months
(immediately post-weight loss), and at 6, 12, 24, and 36 months.
Results: There was a decrease in plasma peptide YY concentrations and an increase
in ghrelin after the 2-month weight-reducing diet, and these values approached
pre-weight-loss values by 6 and 24 months, respectively (P = 0.32 and P = 0.08,
respectively, vs. 0 months). However, there were no differences between the two
weight-maintenance diets. Subjective appetite sensations were not affected by the
weight-reducing diet nor the weight-maintenance diets. While participants regained an
average of ∼50% of the weight they had lost by 36 months, the changes in ghrelin and
peptide YY during the weight-reducing phase did not correlate with weight regain.
1 March 2021 | Volume 8 | Article 640538
Buso et al.
Conclusion: A higher-protein, low-GI diet for weight maintenance does not attenuate
changes in ghrelin or peptide YY compared with a moderate-protein, moderate-GI diet.
Clinical Trial Registry: ClinicalTrials.gov registry ID NCT01777893 (PREVIEW) and ID
NCT02030249 (Sub-study).
Keywords: weight maintenance, appetite, gut hormones, ghrelin, peptide YY
INTRODUCTION
Overweight and obesity are rapidly increasing worldwide, with
the number of people with obesity having more than doubled
since 1980 (1). In 2016, 671 million adults worldwide were
classified as having obesity (2). Overweight and obesity have
multiple adverse health consequences, such as cardiovascular
diseases and type 2 diabetes, which are the leading causes of
death related to high body mass index (3). To mitigate these
diseases, lifestyle management of obesity is necessary. For people
with obesity and diabetes (or a high risk of diabetes), even
moderate weight reduction of 5–10% of initial weight improves
glycemic control (or reduces the risk of developing diabetes) (4,
5). However, lifestyle-based weight-loss interventions are often
ineffective in the long term, resulting in regain of all of the weight
lost in about 50% of individuals by 5 years (6).
There are many possible mechanisms for the difficulty in
maintaining a reduced weight. These include physiological
adaptations, such as decreased energy expenditure and increased
hunger sensations (7–10), associated with increases in circulating
concentrations of the appetite-stimulating hormone, ghrelin,
and reductions in that of the appetite-suppressing hormone,
peptide YY (11–16). These changes in appetite sensations and
gut hormone concentrations after weight loss can persist for 1
year (17–19) to 3 years (20) after weight loss in people who
originally had a body mass index in the overweight or obese
range, providing a possible explanation for the low success rate
of weight maintenance at a reduced body weight. Finding ways to
reduce appetite after weight loss could potentially help to increase
the long-term success of weight-loss interventions.
Some evidence shows that reducing appetite sensations might
be achievable with a weight-loss or weight-maintenance diet that
is higher in protein or lower in glycemic index (GI) than the
diet that is conventionally recommended for health (21–24). For
instance, a 20% higher protein intake (18 vs. 15% of energy)
during a weight-maintenance diet after weight loss caused a 50%
lower weight regain 3 months after weight loss, in association
with higher sensations of satiety (23). Comparatively, a diet with
a low GI seems to increase satiety in the majority of short-term
studies (21, 25). Moreover, a low-GI diet was more effective for
maintenance of a reduced body weight, when combined with a
higher protein intake and when compared to a diet of moderate-
GI and/or moderate-protein content, as demonstrated in the
26-week Diogenes study (26).
Abbreviations: CHO, carbohydrate; GI, glycemic index; HP/LGI, higher
protein/low glycemic index; MP/MGI, moderate protein/moderate glycemic index.
Frontiers in Nutrition | www.frontiersin.org
Appetite Responses During Weight Maintenance
In light of the above considerations, it is possible that a
diet that is higher in protein and low in GI may be able to
attenuate the increase in appetite and associated changes in
circulating gut hormone concentrations seen with weight loss
and may therefore help to promote weight-loss maintenance
in the long term. To our knowledge, this has never been
tested in a randomized control trial. Therefore, the aim of
this study was to evaluate if the appetite-inducing effect
of weight loss can be reversed by a higher-protein, low-
GI vs. a moderate-protein, medium-GI weight-maintenance
diet. This was tested in a sub-study of the PREVIEW
(PREVention of diabetes through lifestyle Intervention and
population studies in Europe and around the World) Study in
Sydney, Australia.
MATERIALS AND METHODS
Participants and Setting
Participants in this sub-study were investigated at the Charles
Perkins Centre Royal Prince Alfred Clinic on the University of
Sydney campus in Camperdown, New South Wales, Australia.
Adults with pre-diabetes [defined by (i) plasma glucose
concentrations of 5.6–6.9 mmol/L when fasted and/or (ii)
impaired glucose tolerance, with plasma glucose concentrations
of 7.8–11.0 mmol/L at 2 h after oral administration of a
standard 75-g glucose dose and a fasting plasma glucose
concentration of <7.0 mmol/L] and a body mass index
of ≥25 kg/m2 were eligible for the PREVIEW randomized
controlled trial in Sydney. Of those participants that started
the trial, those who lost 8% or more of their initial
body weight during the 2-month weight-reducing diet were
eligible to start the subsequent weight-maintenance diet.
Full details of the selection criteria for the PREVIEW
randomized controlled trial have been published previously
(27). All participants gave written informed consent prior to
participating in the PREVIEW randomized controlled trial and
the current sub-study.
Design
The PREVIEW Study was a multinational 3-year study whose
goal was to identify the most efficient lifestyle factors for the
prevention of diabetes in a population of people with pre-
diabetes. The randomized controlled trial of the PREVIEW Study
involved a 36-month intervention, commencing with a weight-
reducing phase (2 months) followed by a weight-maintenance
phase (34 months) as detailed below.
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Buso et al.
Weight-Reducing and Weight-Maintenance
Phases
The 2-month weight-reducing phase entailed a total meal
replacement diet delivering ∼3,400 kJ (800 kcal) per day,
comprising 15–20% of energy from fat (E% fat), 35–40
E% protein, and 45–50 E% carbohydrate (CHO) (Cambridge
Weight Plan© , Ltd, UK). During the weight-maintenance phase,
participants were randomly assigned to either a higher-protein
R
(25 E%) and moderate-CHO (45 E%) diet with a low-GI (GI
≤50) (HP/LGI) or moderate-protein (15 E%) and higher-CHO
(55 E%) diet with a moderate GI (GI ≥56) (MP/MGI). Both diets
were moderate in fat (30 E%). Participants were not given specific
targets for energy intake but were instead encouraged to “eat
to appetite” and to follow a regular meal pattern, with no other
specifications about the timing of eating. In other words, the
weight-maintenance diets were ad libitum for energy. In addition
to randomization for weight-maintenance diets, participants
were randomized to one of two physical activity interventions:
either a high-intensity exercise intervention, or a moderate-
intensity exercise intervention. Due to the small sample size of
this sub-study (136 participants), the impact of physical activity
interventions will not be presented in this paper, albeit analyses
of effects of the two weight-maintenance diets will be adjusted for
the exercise intervention group.
Outcomes and Time Points
For the sub-study reported in this paper, the following outcomes
were measured and analyzed at the following time points: 0
months (pre-weight loss), 2 months (immediately post-weight
loss, which is at the start of the weight-maintenance phase),
and 6, 12, 24, and 36 months (end of the weight-maintenance
phase). Participants were asked to attend our clinical research
facility in the morning, having consumed nothing but water
since midnight. They then underwent different measurements,
as described in detail elsewhere (27). Measurements relevant or
specific to this sub-study are detailed below.
Anthropometric Measurements
Body weight was measured to the nearest 0.1 kg using a
calibrated Tanita BWB-800 digital scale (Wedderburn) and with
participants in light clothing without shoes. Height was measured
to the nearest 0.5 cm with a Harpenden 602VR Stadiometer
(Holtain Limited).
Fasting Appetite Sensations
Fasting sensations of hunger, desire to eat, prospective
consumption (how much food participants felt they could
eat at that time), and fullness were quantified using visual analog
scales printed on paper (28). Each visual analog scale consisted
of a 100-mm horizontal line, where 0 represented “sensation
not felt at all” and 100 represented “sensation felt the greatest.”
Participants were asked to place a vertical mark along each
horizontal line to indicate the strength of the sensation they felt at
that particular time. The intensity of the sensation (distance from
0) was then measured with a ruler, generating a score in the range
of 0–100 mm.
Frontiers in Nutrition | www.frontiersin.org
Appetite Responses During Weight Maintenance
Blood Collection and Sample Storage
For measurement of fasting plasma concentrations of ghrelin and
peptide YY, blood samples were collected into ice-cold EDTA-
treated tubes (Becton Dickinson). Immediately after collection,
samples were plunged up to the neck into wet ice. Plasma was
then obtained by centrifugation of blood samples at 3,200 rpm
(∼1,600 × g) for 10 min at 4◦ C (Eppendorf Centrifuge 5702,
Eppendorf AG). Plasma aliquots were pipetted into CryoPure
tubes (Sarstedt Australia) and immediately stored at −80 C ◦
until analyzed.
Fasting Plasma Concentrations of Ghrelin
and Peptide YY
Concentrations of ghrelin (total) and peptide YY (total)
in plasma samples were measured using commercial
radioimmunoassay kits (Merck Millipore, Billerica, MA,
USA) according to the manufacturer’s instructions. These assays
detect minimum concentrations of 93 pg/ml ghrelin and 20
pg/ml peptide YY. Inter- and intra-assay coefficients of variability
(%CV) were, respectively, 4.0 and 5.4% for ghrelin and 15.0 and
4.6% for peptide YY.
Statistical Analyses
All analyses were by intention-to-treat and were performed
in Statistical Analysis System (SAS) version 9.4 (SAS Institute,
North Carolina, US). Participant characteristics at 0 months (pre-
weight loss) were evaluated both in participants who came to
the final 36-month outcome measurement (“completers”) and
in those who did not (“non-completers”) and are presented as
means (with standard deviation) or—when data were skewed—
as medians [with interquartile range]. To compare completers
and non-completers, Student t-tests were used for normally
distributed variables, Mann–Whitney–Wilcoxon non-parametric
tests were used for skewed variables, and Chi-square tests were
used for categorical variables. To investigate between-group
effects of the weight-maintenance diets over time, intention-
to-treat analyses were performed on all raw outcomes using
a repeated constrained linear mixed model from 2 months
(immediately post-weight loss, which is at the start of the weight-
maintenance phase), with a restricted maximum likelihood. With
this model, the mean of the 2-month (post-weight loss/baseline)
values is constrained (assumed) to be the same for all groups due
to the process of randomization (29). Modeling of the covariance
structure was undertaken to account for the dependent nature
of the data at different time points. An unstructured or spatial
power (SP[POW]) covariate structure was used (because time
points were not equally spaced), and models with the best fit were
presented. Plasma ghrelin and peptide YY concentrations were
log-transformed to improve the fit of the models (assumption
of normality and variance homogeneity of the residuals were
met). The repeated constrained linear mixed models included
the following variables: age, sex, pre-weight loss (0-month)
value, the exercise group to which each participant had been
assigned, and the time∗ diet interaction. As a secondary analysis,
and because of lack of differences between the two weight-
maintenance diets, repeated linear mixed models were fitted to
evaluate changes within the entire population and to compare
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Buso et al. Appetite Responses During Weight Maintenance

FIGURE 1 | Trial flow diagram. The trial involved a 2-month weight-reducing diet consisting of a total meal replacement diet with a prescribed daily energy intake of
3,400 kJ (800 kcal). As per the registered trial design, participants who lost 8% or more of their initial body weight proceeded to a 34-month weight-maintenance diet
involving either a diet with a higher protein (25% of energy) and moderate carbohydrate content (45% of energy) with a low glycemic index (≤50) (HP/LGI) vs. a diet
with a moderate protein (15% of energy) and higher carbohydrate content (55% of energy) with a moderate GI (≥56) (MP/MGI).

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Buso et al. Appetite Responses During Weight Maintenance

TABLE 1 | Characteristics before weight loss of all participants that completed the 2-month weight-reducing diet and lost ≥8% of their initial body weight, subdivided into
those who completed or did not complete the subsequent 34-month weight-maintenance diet to which they were randomized [either a higher protein/low GI (HP/LGI) diet
or a moderate protein/moderate GI (MP/MGI) diet].

Both weight-maintenance diets HP/LGI MP/MGI

a d
Characteristic All Completers Non- All Completers Non- All Completerse Non-
participants (n = 105) completers participants (n = 53) completersd participants (n = 52) completerse
(n = 136) (n =31) (n = 71) (n = 18) (n = 65) (n = 13)

General
Female, % (n) 68.4 (93) 66.7 (70) 74.2 (23) 69.0 (49) 67.9 (36) 72.2 (13) 67.7 (44) 65.4 (34) 76.9 (10)
Age, years 56 [48–62] 56 [50–62] 53 [45–59] 53 [45–62] 57 [45–62] 53 [39–60] 55 [50–61] 56 [50–62] 55 [48–58]
Anthropometrics
Height, m 1.68 (0.09) 1.68 (0.09) 1.67 (0.08) 1.67 (0.09) 1.68 (0.09) 1.67 (0.08) 1.68 (0.09) 1.68 (0.09) 1.67 (0.08)
Weight, kg 100.2 99.4 108.4 100.1 99.4 104.6 100.8 99.0 113.1
[87.2–112.1] [85.9–105.6] [93.2–116.5] [89.4–113.3] [85.4–104.4] [93.2–114.8] [86.3–111.1] [86.1–106.9] [93.7–118.3]
Body mass index, kg/m2 34.8 33.9 37.7 35.0 34.9 36.9 33.9 33.5 40.4
[31.4–39.2] [31.1–37.8] [31.9–43.4] [31.9–38.7] [31.6–37.6] [32.3–43.4] [31.2–39.7] [30.8–39.0] [31.8–44.9]
Weight loss at 2 months, % 11.0 11.1 10.5 11.1 11.2 10.3 10.9 11.0 10.8
[9.8–13.0] [9.9–13.0] [9.7–12.9] [9.8–12.9] [10.2–12.7] [9.7–12.9] [9.7–13.0] [9.8–13.0] [9.1–12.7]
Weight loss at 2 months, kg 11.0 10.8 11.3 11.2 11.3 11.2 10.7 10.7 12.3
[9.1–13.3] [9.1–13.2] [9.4–14.4] [9.4–13.5] [9.4–13.5] [9.4–12.7] [9.1–12.8] [9.0–12.8] [9.7–14.4]
Fasting plasma gut hormone concentrations and appetite sensations
Ghrelin, pg/mlb 859 848 891 880 861 930 824 823 825
[679–1240] [625–1249] [737–1224] [649–1224] [577–1164] [767–1224] [685–1307] [708–1396] [546–1307]
Peptide YY, pg/mlb 249 236 257 255 253 260 233 232 255
[197–305] [191–306] [209–300] [203–318] [197–322] [209–296] [181–293] [181–290] [187–384]
Hunger, mmc 30.0 30.5 27.0 30.0 31.0 20.5 30.0 30.0 30.0
[14.0–49.0] [16.0–50.0] [11.0–45.0] [14.0–49.0] [15.0–49.0] [9.0–44.0] [20.0–51.5] [19.0–52.0] [21.0–45.0]
Desire to eat, mmc 36.5 41.0 25.0 32.0 37.0 25.0 41.0 44.0 34.0
[15.5–58.0] [16.0–60.0] [14.0–46.0] [15.0–60.0] [15.0–61.0] [13.0–44.0] [16.0–57.0] [15.0–57.5] [23.0–47.0]
Prospective consumption, mmc 43.5 45.0 39.0 41.0 42.0 40.0 46.0 46.5 37.0
[27.5–54.5] [25.0–54.0] [18.0–63.0] [25.0–53.0] [27.0–53.0] [18.0–49.0] [30.0–55.0] [31.0–54.5] [23.0–69.0]
Fullness, mmc 32.5 33.0 30.0 29.0 29.0 32.0 33.8 33.5 30.0
[16.0–51.5] [16.0–50.0] [9.0–52.0] [52.0–36.0] [16.0–53.0] [14.0–51.0] [12.0–49.0] [12.0–49.0] [6.0–57.0]

a Mean (standard deviation), median [25–75th percentile] or % (n).

b Valid data on plasma hormone concentrations are available for 93 participants.
c Data for one participant is missing because the participant did not complete the questionnaire.
d Valid data on plasma hormone concentrations are available data for 33 participants in completers and 14 participants in non-completers in the HP/LGI diet.
e Valid data on plasma hormone concentrations are available data for 35 participants in completers and 11 participants in non-completers in the MP/MGI diet.

the data from each time point (i.e., 2, 6, 24, and 36 months)
with the value at 0 months (pre-weight loss, before the weight-
reducing diet). Bonferroni corrections were used to account for
the multiple comparisons.
To investigate whether changes in plasma gut hormone
concentrations correlated with changes in weight during
the weight-reducing diet (as measured from 0 to 2 months)
and during the weight-maintenance diets (as measured
between 2 and 36 months), we undertook correlation analyses
with Spearman’s rank correlation. P-values <0.05 (or <0.01
when Bonferroni adjustments were applied) were considered
statistically significant.
RESULTS
In total, 136 participants achieved 8% or greater weight loss
at the end of the weight-reducing phase and were eligible to
be randomized to one of the two weight-maintenance diets
(Figure 1). Characteristics of participants pre-weight loss (i.e.,
at 0 months) are presented in Table 1. Overall, 68.4% of the
participants were female (n = 93/136). Participants had a median
[interquartile range, IQR] age of 56 [48–62] years, a median
[IQR] body weight of 100.2 [87.2–112.1] kg, and a median [IQR]
body mass index of 34.8 [31.4–39.2] kg/m2 . In total, 105 of the
136 participants at the Sydney site (77.2%) completed the trial
to the final (36-month) time point, 53 out of 71 (74.6%) from
the HP/LGI weight-maintenance diet group, and 52 out of 65
(80.0%) from the MP/MGI weight-maintenance diet group, as
detailed in Figure 1. There were differences in body weight and
body mass index between completers and non-completers before
weight loss, with completers having a lower body weight (99.4 vs.
108.4 kg, P = 0.04) and body mass index (33.9 vs. 37.7 kg/m2 ,
P = 0.02) compared to non-completers at 0 months. There
were no statistically significant differences between completers
and non-completers within each study arm (all P-values >0.05);

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Buso et al. Appetite Responses During Weight Maintenance

however, median pre-weight-loss values were lower for ghrelin

(861 vs. 930 pg/ml, P = 0.33), but higher for hunger (31.0 vs.
20.5 mm, P = 0.10) and desire to eat (37 vs. 25 mm, P = 0.13)
in the completers group vs. the non-completers group within the
HP/LGI group only (Table 1).

Body Weight
At the end of the weight-reducing phase, median [IQR] weight
loss in all participants was 11.0 [9.8–13.0]% of initial body weight
(Table 1). Weight loss was similar between completers and non-
completers, with a median [IQR] weight loss of 11.1 [9.9–13.0]%
vs. 10.5 [9.7–12.9]% of initial body weight, respectively, P = 0.32.
During the weight-maintenance diets, there were no observed
differences in weight between groups (P = 0.30) (Figure 2A
and Table 2). At 36 months, the mean difference (95% CI)
between groups was 0.62 (−1.87–3.12) kg. Overall, participants
experienced partial weight regain, with body weight remaining
lower than pre-weight-loss (0-month) values until the end of the
intervention (P < 0.001 at all time points, Table 3). On average,
participants had a mean overall regain of 48.7% of the weight lost.

Fasting Plasma Gut Hormone

Concentrations and Appetite Sensations
Intention-to-treat analyses revealed no evidence of any overall
difference between the weight-maintenance diets for fasting
plasma concentrations of either gut hormone over the course
of the trial (P = 0.95 and P = 0.22 for ghrelin and peptide
YY, respectively) (Table 2 and Figures 2B,C). During the weight-
reducing phase, there was an increase from pre-weight-loss
values (i.e., from 0-month values) in fasting plasma ghrelin
concentrations, as well as a decrease in fasting plasma peptide
YY concentrations (all P < 0.001) (Table 3). Moreover, the
differences from 0-month values in fasting plasma peptide YY
and ghrelin concentrations were attenuated within 6 and 24
months, respectively (P = 0.32 and P = 0.08, respectively, vs. 0
months) (Table 3). In terms of fasting appetite sensations, there
was no evidence of any differences between the two weight-
maintenance diets (all P-values for the interaction were >0.05, FIGURE 2 | Weight (A) and fasting plasma gut hormone concentrations
as shown in Table 2), and there were also no clear overall changes [Ghrelin (B) and Peptide YY (C)] before, during, and after the weight-reducing
from pre-weight-loss values (i.e., from 0-month values) (Table 3). (gray shaded bar) and weight-maintenance diets of the PREVIEW sub-study
[either a higher protein/low GI (HP/LGI) or a moderate-protein/moderate-GI
(MP/MGI) weight-maintenance diet]. Results of a constrained linear mixed
model (2–36 months) are shown as estimated marginal means (i.e., means
Weight and Fasting Gut Hormone adjusted for age, sex, exercise group, and the value at 0 months) ± 95% CI.
There were no statistically significant differences between the
Correlations weight-maintenance diets at any time point (P-values for the interaction of
There was no correlation between changes in ghrelin or peptide diet*time are shown on each panel). Ghrelin and peptide YY were
YY during the weight-reducing phase and changes in weight log-transformed in the analyses.
during the weight-reducing phase or the subsequent weight-
maintenance phase (data not shown). During the weight-
maintenance phase, however, there was an inverse correlation
between the change in ghrelin and the change in weight, DISCUSSION
with a Spearman correlation coefficient of −0.47 (P <
0.001). In other words, the greater the weight regain during In this study, we observed that a 2-month weight-reducing
the weight-maintenance diets, the greater the attenuation in diet using total meal replacement induced an increase in
ghrelin concentrations. fasting plasma concentrations of the “hunger hormone” ghrelin

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Buso et al. Appetite Responses During Weight Maintenance

TABLE 2 | Body weight, plasma gut hormone concentrations, and fasting appetite sensations with the higher-protein/low-GI (HP/LGI) and moderate-protein/moderate-GI
(MP/MGI) weight-maintenance diets.

Measurement No. HP/LGI No. MP/MGI Mean between-group P-valuea

estimated marginal estimated marginal difference (95% CI)
means (95% CI) means (95% CI)

Weight, kg 0.30
2 mo (all) 136 88.2 (87.9–88.6) – –
6 mo 67 87.4 (86.2–88.6) 59 86.7 (85.5–88.0) 0.66 (−0.93–2.27)
12 mo 64 89.7 (88.0–91.4) 55 89.3 (87.4–91.1) 0.41 (−2.06–2.89)
24 mo 61 93.4 (91.4–95.4) 53 92.1 (90.0–94.2) 1.29 (−1.60–4.18)
36 mo 53 94.1 (92.3–95.8) 52 93.4 (91.6–95.3) 0.62 (−1.87–3.12)
Ghrelin, log pg/ml 0.95
2 mo (all) 93 6.98 (6.92–7.05)
6 mo 42 6.89 (6.81–6.96) 37 6.86 (6.78–6.94) 0.02 (−0.07–0.11)
12 mo 41 6.92 (6.83–7.00) 38 6.87 (6.78–6.96) 0.05 (−0.07–0.17)
24 mo 39 6.87 (6.77–6.96) 36 6.85 (6.76–6.95) 0.02 (−0.12–0.15)
36 mo 33 6.84 (6.74–6.94) 35 6.82 (6.72–6.92) 0.01 (−0.13–0.15)
Peptide YY, log pg/ml 0.22
2 mo (all) 93 5.39 (5.35–5.44)
6 mo 42 5.52 (5.46–5.59) 37 5.48 (5.41–5.55) 0.04 (−0.04–0.13)
12 mo 41 5.47 (5.40–5.54) 38 5.42 (5.35–5.49) 0.06 (−0.04–0.15)
24 mo 39 5.49 (5.42–5.56) 36 5.40 (5.33–5.48) 0.09 (−0.02–0.19)
36 mo 33 5.45 (5.37–5.53) 35 5.52 (5.44–5.59) −0.06 (−0.18–0.05)
Hunger, mm 0.98
2 mo (all) 135 34.7 (30.4–38.9)
6 mo 63 33.9 (28.3–39.6) 56 35.0 (29.1–41.0) −1.1 (−8.9–6.8)
12 mo 64 38.2 (32.1–44.3) 55 40.2 (33.6–46.8) −2.0 (−10.7–6.7)
24 mo 61 39.5 (33.2–45.7) 53 40.4 (33.7–47.1) −0.9 (−9.9–8.2)
36 mo 53 37.6 (31.4–43.9) 52 40.1 (33.7–46.5) −2.5 (−11.2–6.2)
Desire to eat, mm 0.75
2 mo (all) 135 42.9 (38.8–47.0)
6 mo 64 40.0 (35.0–45.0) 57 42.1 (36.9–47.3) −4.2 (−13.0–4.6)
12 mo 64 43.4 (37.7–49.1) 55 44.7 (38.1–51.2) −0.76 (−8.9–7.3)
24 mo 61 43.4 (37.7–49.1) 53 44.1 (38.1–50.2) 1.4 (−6.9–9.7)
36 mo 53 41.3 (35.3–47.3) 52 39.8 (33.7–45.9) −2.1 (−9.0–4.73)
Prospective consumption, mm 0.99
2 mo (all) 135 41.1 (38.0–44.2)
6 mo 64 43.4 (39.8–47.1) 57 43.0 (39.2–46.8) 0.4 (−4.3–5.2)
12 mo 64 43.3 (39.0–47.6) 55 43.3 (38.7–47.9) −0.0 (−5.9–5.8)
24 mo 61 45.1 (40.6–49.5) 53 44.7 (39.9–49.4) 0.4 (−5.7–6.5)
36 mo 53 42.4 (37.5–47.2) 52 40.5 (35.6–45.4) 1.8 (−4.9–8.6)
Fullness, mm 0.26
2 mo (all) 135 33.7 (29.9–37.6)
6 mo 64 29.7 (24.2–35.2) 57 36.4 (30.6–42.1) −6.6 (−14.1–0.8)
12 mo 64 33.8 (27.9–39.8) 55 33.7 (27.4–40.1) 0.1 (−8.5–8.7)
24 mo 61 33.5 (27.9–39.1) 53 39.0 (33.1–45.0) −5.5 (−13.5–2.4)
36 mo 53 38.8 (32.5–45.1) 52 39.3 (32.9–45.7) −0.5 (−9.2–8.1)

a P-values for the interaction of diet*time in the constrained linear mixed model (2–36 months), adjusted for age, sex, physical activity, and value at 0 months (pre-weight loss).

and a decrease in that of the “satiety hormone” peptide
YY, with no change from pre-weight-loss values in appetite
sensations. However, there were no differences in gut hormone
concentrations or appetite sensations between the two 34-month
weight-maintenance diets differing in protein content and GI.
In both weight-maintenance diets, the changes in plasma gut
hormone concentrations induced by weight loss were attenuated
within 6–24 months, without full weight regain.
Several trials have observed alterations in circulating
concentrations of appetite-regulating gut hormones such as

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Buso et al. Appetite Responses During Weight Maintenance

TABLE 3 | Body weight, plasma gut hormone concentration and fasting appetite sensations of participants in both groups, pooled into a single group.

Measurement No. Estimated pooled means Mean difference from P-valuea

(95% CI) pre-weight loss (0-mo) values (95% CI)

Weight, kg
0 mo 136 99.6 (96.3–103.0) – –
2 mo 136 88.1 (85.1–91.2) −11.5 (−12.0 to −11.0) <0.001
6 mo 126 87.0 (83.9–90.1) −12.7 (−13.6 to −11.7) <0.001
12 mo 119 89.4 (86.2–92.6) −10.3 (−11.6 to −8.9) <0.001
24 mo 114 92.7 (89.3–96.1) −6.9 (−8.4 to −5.5) <0.001
36 mo 105 93.7 (90.4–96.9) −6.0 (−7.3 to −4.7) <0.001
Ghrelin, log pg/ml
0 mo 93 6.76 (6.65–6.86) – –
2 mo (all) 93 6.99 (6.88–7.09) 0.23 (0.19–0.27) <0.001
6 mo 79 6.88 (6.77–6.98) 0.12 (0.05–0.19) 0.001
12 mo 79 6.90 (6.79–7.00) 0.14 (0.04–0.23) 0.004
24 mo 75 6.87 (6.75–6.98) 0.11 (−0.01–0.23) 0.08
36 mo 68 6.83 (6.71–6.95) 0.07 (−0.07–0.21) 0.31
Peptide YY, log pg/ml
0 mo 93 5.49 (5.43–5.55) – –
2 mo 93 5.41 (5.35–5.47) −0.08 (−0.12 to −0.04) <0.0001
6 mo 79 5.52 (5.46–5.59) 0.03 (−0.03–0.09) 0.32
12 mo 79 5.46 (5.4–5.53) −0.03 (−0.10–0.05) 0.49
24 mo 75 5.45 (5.38–5.52) −0.04 (−0.13–0.05) 0.39
36 mo 68 5.49 (5.42–5.56) 0.0 (−0.09–0.10) 0.95
Hunger, mm
0 mo 135 34.2 (30–38.4) – –
2 mo 135 33.9 (29.1–38.6) −0.4 (−4.9–4.2) 0.88
6 mo 119 33.8 (29–38.7) −0.4 (−4.8–4.1) 0.86
12 mo 119 38.4 (33.3–43.5) 4.2 (−0.6–8.9) 0.08
24 mo 114 38.9 (33.8–44) 4.7 (−0.2–9.5) 0.06
36 mo 105 38.3 (33.5–43) 4.0 (−0.9–9) 0.11
Desire to eat, mm
0 mo 136 39.6 (34.9–44.2) – –
2 mo 135 42.2 (37.7–46.7) 2.6 (−2.3–7.5) 0.29
6 mo 121 40.2 (35.9–44.5) 0.6 (−3.7–4.9) 0.77
12 mo 119 41.6 (36.6–46.6) 2.0 (−3.1–7.2) 0.43
24 mo 114 43.1 (38.5–47.6) 3.5 (−1.6–8.6) 0.17
36 mo 105 40.0 (35.5–44.6) 0.5 (−4.8–5.7) 0.86
Prospective consumption, mm
0 mo 136 43.4 (39.6–47.2) – –
2 mo 135 41.3 (37.7–45) −2.0 (−5.5–1.4) 0.25
6 mo 121 43.5 (40.1–46.9) 0.2 (−3.2–3.5) 0.93
12 mo 119 43.6 (39.7–47.4) 0.2 (−3.5–3.9) 0.91
24 mo 114 45.2 (41.3–49) 1.8 (−2.0–5.6) 0.36
36 mo 105 41.7 (37.9–45.6) −1.6 (−5.6–2.3) 0.42
Fullness, mm
0 mo 136 33.8 (29.6–38) – –
2 mo 135 34.0 (29.7–38.3) 0.2 (−4–4.4) 0.93
6 mo 121 33.1 (28.7–37.5) −0.7 (−5.7–4.2) 0.77
12 mo 119 34.1 (29.4–38.8) 0.2 (−4.7–5.1) 0.93
24 mo 114 36.3 (31.9–40.8) 2.5 (−2.4–7.4) 0.31
36 mo 105 39.3 (34.4–44.2) 5.4 (0.2–10.7) 0.04

a P-values for the linear mixed model (0–36 months) without an interaction term for the weight-maintenance diets [i.e., P-value for the difference from pre-weight loss (0-month) values;
per test α = 0.01 after Bonferroni correction].

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Buso et al.
ghrelin and peptide YY after weight loss and during weight
maintenance in adults with overweight and obesity (16–20). In
these trials, ghrelin responses are rather consistent in that most
trials showed statistically significant increases in fasting and
post-prandial ghrelin concentrations after weight loss (17–20),
while only one trial showed no statistically significant changes
from pre-weight-loss values (16). In contrast, published results
for peptide YY are more equivocal, as researchers have observed
various responses to weight loss: a decrease in both fasting
and postprandial concentrations (17), a decrease in fasting
concentrations with no change in post-prandial concentrations
(16), a decrease in fasting concentrations with an increase in
post-prandial concentrations (18), or no changes in either fasting
or post-prandial concentrations of peptide YY after weight loss
(19). These hormonal changes led to the general hypothesis that
“compensatory mechanisms” of weight loss-induced increases in
ghrelin, with or without decreases in peptide YY, could be drivers
of weight regain. Furthermore, while some of these trials showed
sustained changes in appetite sensations and gut hormone
concentrations that were still apparent when measured at 1
and 3 years after weight loss (17–20), the degree to which these
sustained changes were attenuated during weight maintenance
after weight loss varied between appetite sensations, hormones,
and trials (16–20). For instance, while some trials showed no
attenuation of the weight loss-induced increases in hunger
(16, 17, 19, 20) or hormonal changes (17, 19) during a weight-
maintenance phase, others showed partial attenuation of the
increased ghrelin (18, 20) or reduced peptide YY concentrations
(18, 20) during weight maintenance.
In line with some of the above-mentioned findings, we too
showed that gut hormone responses to weight loss could be
temporary, as we observed an attenuation of the changes, with
values similar to pre-weight-loss values after 6–24 months.
However, we hypothesized that even though physiological
changes due to weight loss might occur, potentially causing
participants to feel more hungry and thus more prone to
weight regain, a higher-protein/low-GI diet might attenuate
these weight loss-induced changes. Yet, we did not observe any
differences in appetite sensations or gut hormone concentrations
between the two weight-maintenance diets under investigation
in our trial. This finding is at apparent odds with studies
showing that a higher-protein/low-carbohydrate (23, 26) or
lower-carbohydrate/low-GI diet (30) is effective in reducing
body weight (23, 26, 30), reducing appetite sensations (23), and
regulating circulating gut hormone concentrations (23, 30). The
Diogenes study demonstrated that a combined higher-protein
(25 vs. 13% of energy as protein) and low-GI weight-maintenance
diet was the most effective for body weight maintenance during
the 26-week intervention, compared to diets with either or
both of a lower protein content or higher GI (26). Similarly,
a 20% higher protein intake (18 vs. 15% of energy as protein)
during weight maintenance caused higher sensations of satiety
and a 50% lower weight regain 3 months after weight loss (23).
However, in line with our findings, a recent trial, published in
2020, showed that two isoenergetic weight-maintenance diets
that differed in protein, fiber, and fat content (a “higher-satiety
diet” vs. a “lower-satiety diet”) were no different from each other
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Appetite Responses During Weight Maintenance
in terms of effects on fasting gut hormone concentrations (31).
A reason that may explain the discrepancy in findings might
be the absolute protein content of the weight-maintenance diets
(22) and differences in compliance (32). Specifically, although
the target protein content of our moderate protein diet, as a
percent of energy (15%), was similar to that of other studies
(23, 26), the actual protein intake was ∼19% of energy intake
(32). Indeed, the moderate protein group in our study showed a
protein intake above 0.8 g per kg of body weight, compared with
0.6 g per kg body weight in other studies (22, 23, 26). Similarly,
in the recent study mentioned above (31), the percent of energy
intake as protein was also around 17% in both groups, equivalent
to ∼0.8 g per kg of body weight, based on average pre-weight-loss
body weights. According to Soenen et al. (22), a dietary protein
intake of 0.8 g per kg of body weight is sufficient for body weight
maintenance. This may explain the lack of differences between
our two weight-maintenance diets in terms of weight change,
appetite, and gut hormone concentrations.
As changes in circulating gut hormone concentrations during
weight loss have been hypothesized to explain the difficulty
in maintaining a diet-induced reduction in body weight, we
expected to find statistically significant correlations between
hormonal changes during the weight-reducing diet and the
amount of weight regained during the weight-maintenance
diets in this trial. Instead, we observed no correlation
between hormonal changes during the weight-loss diet and
subsequent weight regain, implying that changes in circulating
concentrations of gut hormones may not predict the extent of
weight regain after weight loss and refeeding. This was first
suggested by Nymo and colleagues in 2018 (33), leading that
team to hypothesize that gut hormone changes during weight loss
could be viewed not as a compensatory mechanism to restore
body weight, but instead as a normalization toward values seen
in people of a healthy weight, as recently reviewed by Martins
et al. (34). Indeed, adults with overweight and obesity have
been shown to have lower circulating concentrations of ghrelin
and perturbed concentrations of peptide YY compared to adults
with a normal weight (19, 35, 36). Recently, DeBenedictis et al.
(37) showed an increase in plasma ghrelin concentrations in
adults with overweight or obesity after weight loss, to values that
were not discernibly different from people of normal weight.
This finding provided further support for the hypothesis that
gut hormone changes after weight loss—at least for ghrelin—
might be adiposity signals rather than compensatory signals.
In other words, lower circulating ghrelin concentrations signal
higher adiposity, with concentrations being “restored” to higher
values upon weight loss, rather than an increase in ghrelin
concentrations upon weight loss being compensatory signals
that promote weight regain. In keeping with the hypothesis of
ghrelin as an adiposity signal, we observed that weight regain
during the weight-maintenance diets was correlated with a
reduction of fasting plasma ghrelin concentrations during the
same time, indicating that weight regain may contribute to
the reestablishment of pre-weight-loss ghrelin concentrations.
In other words, the changes in body weight during the weight
reduction and weight-maintenance phases may have contributed
to the observed changes in plasma hormone concentrations,
9 March 2021 | Volume 8 | Article 640538
Buso et al.
rather than changes in hormone concentrations contributing
to changes in body weight. It is therefore likely that the
partial weight regain observed in our trial during the weight-
maintenance diets (48.7%) was not mediated by the gut hormone
changes with weight loss, but might instead be driven by other
biological, behavioral, or environmental factors (37).
Our current observations of lack of any increase in fasting
appetite sensations during the weight-loss diet (2 months)
are in line with past research showing no change or a
reduction in hunger while on a total meal replacement diet
(38). However, our findings of this lack of increase in appetite
sensations persisting into the weight-maintenance phase contrast
with others who have shown consistent increases in both
fasting and postprandial hunger sensations during a weight-
maintenance phase after weight loss (16, 17, 19, 20). Only
one research team has repeatedly shown an increase in
postprandial fullness concomitant with increased postprandial
hunger following refeeding (19, 37). Causes of conflicting
findings between studies might be due to methodological
factors such as the difficulty in using a visual analog scale
to accurately measure appetite sensations (39). Additionally,
we only focused on fasting appetite sensations in our study,
which limits our view on appetite regulation. Moreover, the
complexity of the appetite-regulation system and the different
mechanistic pathways involved might also cause individuals to
react differently to energy restriction and weight maintenance
and might also be a likely explanation of the equivocal
findings (40, 41).
Further to the lack of evidence for any differences between the
weight-maintenance diets tested in this randomized controlled
trial, our study has important clinical implications. We showed
that a weight-reducing diet is not necessarily associated with
an increase in appetite sensations and that changes in plasma
concentrations of appetite-regulating gut hormones during
weight loss (at least the two key hormones investigated
in this study—ghrelin and peptide YY—other hormones,
such as leptin, were not investigated) may approach pre-
weight-loss levels within 6–24 months without regain of
all the weight that was lost but do not appear to drive
weight regain. It is likely that other biological, behavioral, or
environmental factors are involved in weight regain. Thus,
while people with obesity may experience biological changes
in appetite regulation when losing weight, these changes may
reflect a restoration of biology to that associated with a
healthier body weight. In other words, these biological changes
may not be the cause of weight changes and consequently
might not necessarily prevent maintenance of the reduced
body weight.
In conclusion, in this study of the long-term (up to 3-year)
effects of weight-maintenance diets on appetite sensations
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DATA AVAILABILITY STATEMENT
The original contributions presented in the study are included
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ETHICS STATEMENT
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Conflict of Interest: RS serves on the Nestlé Health Science Optifast
R
TM
VLCDTM Advisory Board. JB-M is the President of the Glycemic Index
Foundation (a non-profit food endorsement program), oversees a glycemic index
testing service at the University of Sydney and is the author of books about the
glycemic index, food and healthy eating. AS owns 50% of the shares in Zuman
International, a company which receives royalties for books she has written about
weight management and payments for presentations at industry conferences. She
has also received presentation fees and travel reimbursements from Eli Lilly and
Co, the Pharmacy Guild of Australia, Novo Nordisk, the Dietitians Association
of Australia, Shoalhaven Family Medical Centres, the Pharmaceutical Society
of Australia, and Metagenics, and served on the Nestlé Health Science Optifast
VLCD advisory board from 2016 to 2018. FA is a director of the Glycemic Index
Foundation (a non-profit food endorsement program), manages a glycemic index
testing service at the University of Sydney, and is a co-author of books about the
Frontiers in Nutrition | www.frontiersin.org
Appetite Responses During Weight Maintenance
glycemic index. Finally, Cambridge Weight Plan© , Ltd, UK provided all meal
replacement products used at all sites of the PREVIEW Study. The commercial
and funding sponsors had no role in the design of the study; in the collection,
analyses, or interpretation of data; in the writing of the manuscript, nor in the
decision to publish the results.
The remaining authors declare that the research was conducted in the absence of
any commercial or financial relationships that could be construed as a potential
conflict of interest.
Copyright © 2021 Buso, Seimon, McClintock, Muirhead, Atkinson, Brodie, Dodds,
Zibellini, Das, Wild-Taylor, Burk, Fogelholm, Raben, Brand-Miller and Sainsbury.
This is an open-access article distributed under the terms of the Creative Commons
Attribution License (CC BY). The use, distribution or reproduction in other forums
is permitted, provided the original author(s) and the copyright owner(s) are credited
and that the original publication in this journal is cited, in accordance with accepted
academic practice. No use, distribution or reproduction is permitted which does not
comply with these terms.
12 March 2021 | Volume 8 | Article 640538